Over 500,000 strokes occur in this country annually, causing significant disability and death. Only one treatment, recombinant tissue plasminogen activator (rt-PA), is currently approved for stroke. However, just about 3% of the patients receive it, probably because the time-window for therapy is brief (3 hours or less). Therefore, there is a great need for effective neuroprotective agents that could be given alone or in conjunction with thrombolytic agents. Furthermore, prophylactic neuroprotective use may be indicated in certain clinical settings. Each year, in the United States alone, 600,000 adults and 12,000 children undergo open heart operations utilizing cardiopulmonary bypass, during which the brain is subjected to periods of ischemia. Despite advances in surgical procedures and shortening of the ischemic event, CNS dysfunction remains a leading cause of morbidity and mortality in these patients. Because the exact timing of the ischemic insult is known ahead of time in these patients, the potential exists to significantly reduce myocardial damage by pre-treatment with agents that protect the brain from ischemia-reperfusion damage prior to surgery. Our HYPOTHESIS is that select protein kinase C (PKC) isozymes play an important (positive and/or negative) role in the various stages of response of the brain to ischemic insult. Using isozyme-specific inhibitor and activator peptides that we have developed, we plan to; determine which PKC isozymes are activated following cerebral ischemia and when does that occur, and determine whether inhibition or activation of these isozymes can provide protection from ischemic reperfusion damage to the brain. These studies will demonstrate the effectiveness of in vivo delivery of PKC regulating peptides for the treatment of ischemic reperfusion injury of the CNS. Should the treatment be found efficacious and safe, these peptide regulators of PKC activity may be useful for the treatment of stroke and brain ischemia in humans.